Propofol is an anaesthetic that can be used to induce and maintain general anaesthesia and for sedation. Propofol is used as an anaesthetic in both medical and veterinary applications. Injectable anaesthetics such as propofol must be administered directly into the blood stream. Propofol is a rapidly acting intravenous agent that produces anaesthesia of snort duration without excitatory side effects. Recovery from anaesthesia is smooth and rapid, and is unaffected by prolonged or repeat administration.
Water is generally the solvent of choice for parenteral formulations. Anaesthetic agents are generally lipid soluble molecules, as the drug must possess sufficient lipid solubility to cross the blood-brain barrier and exert its action. However, highly lipid soluble molecules are generally poorly soluble in water and thus are difficult to formulate for intravenous injection. Propofol is a hydrophobic water-insoluble oil. Although for some anaesthetics it may be possible to obtain a water-soluble salt of the anaesthetic agent that releases a lipid soluble free base in vivo, to date this has not proved feasible for propofol and no such compound is commercially available.
To develop an aqueous formulation of propofol, non-aqueous solubilising aids, eg organic solvents, must be used in order to obtain a stable, convenient parenteral dosage form. The chosen solubilising aid should have minimal toxic, irritating and sensitising potential. The solubilising aids should have no or minimal inherent pharmacological activity themselves, and should not adversely affect the pharmacological activity of the propofol.
Various solvents have been used previously. However, whilst use of a single solvent may be adequate to solubilise the propofol, generally the solvent must be present in high concentrations, with attendant toxic potential. Such formulations also have the disadvantage that, upon subsequent dilution with many commonly used pharmaceutical intravenous fluids, the propofol will precipitate out of solution as the drug's solubility in the solvent system is exceeded.
Propofol has been solubilised with Cremophor EL (polyethylene glycol triricinoleate 35) and presented in aqueous formulation (U.S. Pat. No. 4,452,817; U.S. Pat. No. 4,056,635). However, such formulations present a risk of anaphylactoid reactions and demonstrate a high incidence of pain on injection.
Emulsions of propofol have also been utilised. The majority of such formulations utilise some form of oil-in-water emulsion or encapsulation of propofol in order to deliver the anaesthetic agent to the patient.
Commercially available propofol formulations are all oil-in-water emulsions comprising 1% propofol in soya bean oil, egg phosphatide and glycerol. Disadvantages of the commercially available formulations of propofol are that they have potential for elevating serum triglycerides when administered to patients with impaired fat metabolism and/or for extended periods of time due to the high lipid content of the formulation. Furthermore, dilution of such formulations prior to administration is restricted due to the nature of the emulsion. Moreover, such formulations present a risk of bacterial contamination with rapid growth of bacteria due to the lack of antimicrobial preservatives and high nutritive value of the formulation. Any broached container must be used within a short period of time or discarded due to the risk of microbial contamination and growth. Further, such formulations are not suitable for terminal sterilisation by moist heat given the heat-sensitive nature of the excipients.
None of the known formulations are suitable for infinite dilution with water or commonly used infusion fluids.
Clinically, it would be advantageous to formulate an injectable propofol formulation that is a homogenous solution of the drug in an aqueous based pharmaceutically acceptable solvent system free from fat, which can be administered by intravenous bolus injection, and which can be diluted infinitely with commonly used fluids. In addition, the formulation should not present a risk of anaphylactoid reactions in susceptible individuals, as is the case with Cremophor-based formulations.